Embryonic striatal neurons from Niemann-Pick type C mice exhibit defects in cholesterol metabolism and neurotrophin responsiveness

Niemann-Pick type C (NP-C) disease is a progressive and fatal neuropatholog ical disorder previously characterized by abnormal cholesterol metabolism i n peripheral tissues. Although a defective gene has been identified in both humans and the npc(nih) mouse model of NP-C disease, how this leads to abn ormal neuronal function is unclear. Here we show that whereas embryonic str iatal neurons from npc(nih) mice can take up low density lipoprotein-derive d cholesterol, its subsequent hydrolysis and esterification are significant ly reduced. Given the importance of cholesterol to a variety of signal tran sduction mechanisms, we assessed the effect of this abnormality on the abil ity of these neurons to respond to brain-derived neurotrophic factor (BDNF) . In contrast to its effects on wild type neurons, BDNF failed to induce au tophosphorylation of the TrkB receptor and to increase neurite outgrowth in npc(nih) neurons, despite expression of TrkB on the cell surface. The resu lts suggest that abnormal cholesterol metabolism occurs in neurons in the b rain during NP-C disease, even at embryonic stages of development prior to the onset of phenotypic symptoms. Moreover, this defect is associated with a lack of TrkB function and BDNF responsiveness, which may contribute to th e loss of neuronal function observed in NP-C disease.